The Antigen‐Specific Response of NK Cells to SARS‐CoV‐2 Correlates With KIR2DS4 Expression

ABSTRACT Natural killer (NK) cells play a pivotal role in the immune response against viral infections, including SARS‐CoV‐2. However, our understanding of memory NK cell responses in the context of SARS‐CoV‐2 remains limited. To address this, we investigated the memory‐like response of NK cells to SARS‐CoV‐2 peptides, presented by autologous cells. Blood samples from 45 donors underwent analysis for SARS‐CoV‐2 IgG antibodies, categorizing them into four groups based on the antibody kind and level. NK cells from SARS‐CoV‐2‐experienced donors demonstrated enhanced degranulation and activation levels, IFNγ production and proliferative potential in response to SARS‐CoV‐2 peptides. Investigation of highly proliferating NK cells demonstrated the formation of distinct clusters depending on the SARS‐CoV‐2 peptide supplementation and the donor group. RNA sequencing revealed differential gene expression patterns, highlighting metabolism, protein transport, and immune response genes. Notably, KIR2DS4 expression correlated with enhanced IFNγ production, degranulation and proliferation levels, suggesting a role in SARS‐CoV‐2 recognition. Collectively, these findings provide detailed insights into antigen‐specific NK cell responses to SARS‐CoV‐2 peptides, indicating potential mechanisms underlying NK cell activation in antiviral immunity.